To be maximally effective, therapy of cancer must be directed against both the resting stem cells and the proliferating cells of the cancer. The cell populations of both normal and cancer tissues consist of resting stem cells, proliferating transit-amplifying cells, terminally differentiating cells and dying (apoptotic) cells. The difference between normal tissue renewal and growth of cancers is that some of the transit-amplifying cells in the cancer population do not mature into terminally differentiating cells, but instead continue to proliferate and do not die (maturation arrest). Because of this the number of cancer cells increase, whereas the cell population of normal tissues remains a relatively constant. Conventional radiation treatment and chemotherapy kill the actively proliferating transit- amplifying cells of the cancer. Differentiation therapy, using specific targeted inhibitors of activation, effectively induces differentiation of the proliferating transitamplifying cancer cells. However, even if the proliferating cancer cells are completely inhibited or eliminated, the cancer stem cells may restore the transit-amplifying population, so that clinical remission is usually temporary. The hypothesis presented in this paper is that successful cancer therapy must be directed against both the resting stem cells and the proliferating cells of the cancer. This may be possible if specific stem cell signals are inhibited using gene therapy, while at the same time attacking proliferating cells by conventional radiation treatment or chemotherapy. With advances in approaches using specific inhibitory RNA, such combination therapy may now be possible, but critical problems in delivering the inhibitory effect specifically to the cancer stem cells have yet to be worked out.
Stem cells, differentiation, leukemia, teratocarcinoma, carcinogenesis, retinoic acid, small inhibitory RNA, signal transduction
Wadsworth Center and Ordway Research Institute, New York State Dept. of Health, Empire State Plaza, Albany, NY 12201, USA.